This R21 project proposes to develop a novel pharmacological-EEG probe of central corticotropin- releasing hormone (CRH) receptor function suitable for clinical research. The long-term objective of this work is a mechanism-based treatment approach to stress related psychiatric disorders. The relative impermeability of the blood brain barrier to CRH is an obstacle to testing mechanistic theories regarding central CRH function in humans. The novelty of this work lies in its administration of the CRH neuropeptide to the olfactory epithelium in order to quantitatively test pharmacodynamic and pharmacokinetic properties of intranasally administered CRH in healthy controls and remitted depressives. We aim to conduct two parallel, placebo-crossover pharmacodynamic studies of 1. intranasal and 2. intravenous CRH. We are primarily interested in the effect of intranasal CRH (vs. placebo) on a quantitative measurement of brain activity (event related EEG) and startle reflex (EMG). Preliminary human data from our laboratory are consistent with such effects. The public health relevance of the study is two-fold. Firstly, obtaining a pharmacodynamic probe of CRH function will permit mechanistic investigations of depressive disorder. Secondly, a pharmacodynamic readout CRH function may help to quantitatively guide future anti-CRH receptor based treatments. PUBLIC HEALTH RELEVANCE: The objective of this R21 proposal is to test a probe of central CRH receptor function in healthy adult male and female subjects. The probe combines intranasal CRH challenge with EEG measures of brain cortical activity. In order to understand the kinetics of the intranasal probe, an intravenous CRH challenge will also be performed, to provide comparison data.